Search for a pharmacological intervention to mimic the beneficial effects of caloric restriction in C. elegans

• Grant number: 12/04064-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2012
• End date: December 31, 2014
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Marcelo Alves da Silva Mori
• Grantee: Vitor Neves Sato
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 10/52557-0 - Identification of mechanisms responsible for beneficial effects of calorie restriction, AP.JP

Abstract

Calorie restriction promotes beneficial health effects and prolongs lifespan in different species, from yeast to primates. Our group recently identified an evolutionarily conserved phenomenon that is directly associated with the aging process and can be reversed by caloric restriction. This phenomenon is characterized by progressive dysfunction of the RNA interference (RNAi) pathway in tissues responsible for the cell's non-autonomous control of life expectancy, including the adipose tissue. In this project, we hypothesized that the use of drugs that promote RNAi may serve as mimetics of the effects of caloric restriction. Thus, we use the C. elegans model to: 1) evaluate the lifespan and stress resistance of animals in response to treatment with Enoxacin, a broad-spectrum antibiotic that was shown to enhance the RNAi efficiency in eukaryotic cells, and (2) investigate the interaction between the effects of Enoxacin, the RNAi pathway, and caloric intake. Initially, we will determine the mean and the maximum lifespan of wild-type C. elegans (N2) cultured in a growth medium containing Enoxacin. We will also evaluate the survival of the animals in response to heat stress (33°C), a paradigm that accelerates aging and serves as a surrogate for a "disease" model in this species. To test the dependency of the RNAi pathway, we will test the effect of Enoxacin on the dcr-1 loss of function mutant strain, which is unable to process functional RNAi. Finally, we will test the effect of Enoxacin on the eat-2 mutant, which has impaired pharyngeal pumping and therefore serves as a genetic model of caloric restriction. We, therefore, intend to propose the use of Enoxacin as a pharmacological intervention to mimic the beneficial effects of caloric restriction, thereby decoupling the metabolic and behavioral burdens that often accompany caloric self-restraint.(AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PINTO, SILAS; SATO, VITOR N.; DE-SOUZA, EVANDRO A.; FERRAZ, RAFAEL C.; CAMARA, HENRIQUE; PINCA, ANA PAULA F.; MAZZOTTI, DIEGO R.; LOVCI, MICHAEL T.; TONON, GUILHERME; LOPES-RAMOS, CAMILA M.; et al. Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis. REDOX BIOLOGY, v. 18, p. 84-92, SEP 2018. (12/04064-0, 15/04264-8, 17/04377-2, 15/01316-7, 14/10814-8, 17/01184-9, 12/24490-4, 10/52557-0, 14/25270-3, 14/25068-0)

FERRAZ, RAFAEL C.; CAMARA, HENRIQUE; DE-SOUZA, EVANDRO A.; PINTO, SILAS; PINCA, ANA PAULA F.; SILVA, RICHARD C.; SATO, VITOR N.; CASTILHO, BEATRIZ A.; MORI, MARCELO A.. IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans. BMC Biology, v. 14, OCT 7 2016. (10/52557-0, 15/01316-7, 12/24490-4, 14/25270-3, 14/10814-8, 14/17145-4, 09/52047-5, 15/04264-8, 12/04064-0, 14/25068-0)